Beauvais Genevieve, Bode Nicole M, Watson Jaime L, Wen Hsiang, Glenn Kevin A, Kawano Hiroyuki, Harata N Charles, Ehrlich Michelle E, Gonzalez-Alegre Pedro
Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
Department of Neurology and.
J Neurosci. 2016 Oct 5;36(40):10245-10256. doi: 10.1523/JNEUROSCI.0669-16.2016.
Dystonia type 1 (DYT1) is a dominantly inherited neurological disease caused by mutations in TOR1A, the gene encoding the endoplasmic reticulum (ER)-resident protein torsinA. Previous work mostly completed in cell-based systems suggests that mutant torsinA alters protein processing in the secretory pathway. We hypothesized that inducing ER stress in the mammalian brain in vivo would trigger or exacerbate mutant torsinA-induced dysfunction. To test this hypothesis, we crossed DYT1 knock-in with p58(IPK)-null mice. The ER co-chaperone p58(IPK) interacts with BiP and assists in protein maturation by helping to fold ER cargo. Its deletion increases the cellular sensitivity to ER stress. We found a lower generation of DYT1 knock-in/p58 knock-out mice than expected from this cross, suggesting a developmental interaction that influences viability. However, surviving animals did not exhibit abnormal motor function. Analysis of brain tissue uncovered dysregulation of eiF2α and Akt/mTOR translational control pathways in the DYT1 brain, a finding confirmed in a second rodent model and in human brain. Finally, an unbiased proteomic analysis identified relevant changes in the neuronal protein landscape suggesting abnormal ER protein metabolism and calcium dysregulation. Functional studies confirmed the interaction between the DYT1 genotype and neuronal calcium dynamics. Overall, these findings advance our knowledge on dystonia, linking translational control pathways and calcium physiology to dystonia pathogenesis and identifying potential new pharmacological targets.
Dystonia type 1 (DYT1) is one of the different forms of inherited dystonia, a neurological disorder characterized by involuntary, disabling movements. DYT1 is caused by mutations in the gene that encodes the endoplasmic reticulum (ER)-resident protein torsinA. How mutant torsinA causes neuronal dysfunction remains unknown. Here, we show the behavioral and molecular consequences of stressing the ER in DYT1 mice by increasing the amount of misfolded proteins. This resulted in the generation of a reduced number of animals, evidence of abnormal ER protein processing and dysregulation of translational control pathways. The work described here proposes a shared mechanism for different forms of dystonia, links for the first time known biological pathways to dystonia pathogenesis, and uncovers potential pharmacological targets for its treatment.
1型肌张力障碍（DYT1）是一种由TOR1A基因突变引起的显性遗传性神经疾病，TOR1A基因编码内质网（ER）驻留蛋白扭转蛋白A。此前大多在细胞系统中完成的研究表明，突变型扭转蛋白A会改变分泌途径中的蛋白质加工过程。我们推测，在哺乳动物大脑中体内诱导内质网应激会引发或加剧突变型扭转蛋白A诱导的功能障碍。为了验证这一假设，我们将DYT1基因敲入小鼠与p58（IPK）基因敲除小鼠进行杂交。内质网共伴侣蛋白p58（IPK）与BiP相互作用，并通过帮助折叠内质网货物来协助蛋白质成熟。其缺失会增加细胞对内质网应激的敏感性。我们发现，DYT1基因敲入/p58基因敲除小鼠的产生数量低于此次杂交预期，这表明存在影响生存能力的发育相互作用。然而，存活的动物并未表现出异常的运动功能。对脑组织的分析发现，DYT1大脑中eiF2α和Akt/mTOR翻译控制途径失调，这一发现已在第二种啮齿动物模型和人类大脑中得到证实。最后，一项无偏蛋白质组学分析确定了神经元蛋白质组中的相关变化，表明内质网蛋白质代谢异常和钙调节失调。功能研究证实了DYT1基因型与神经元钙动力学之间的相互作用。总体而言，这些发现增进了我们对肌张力障碍的认识，将翻译控制途径和钙生理学与肌张力障碍发病机制联系起来，并确定了潜在的新药理学靶点。
1型肌张力障碍（DYT1）是遗传性肌张力障碍的不同形式之一，遗传性肌张力障碍是一种以不自主、致残性运动为特征的神经疾病。DYT1由编码内质网（ER）驻留蛋白扭转蛋白A的基因突变引起。突变型扭转蛋白A如何导致神经元功能障碍尚不清楚。在这里，我们通过增加错误折叠蛋白的数量来展示DYT1小鼠内质网应激的行为和分子后果。这导致产生的动物数量减少，这是内质网蛋白质加工异常和翻译控制途径失调的证据。本文所述的工作提出了不同形式肌张力障碍的共同机制，首次将已知的生物学途径与肌张力障碍发病机制联系起来，并揭示了其治疗的潜在药理学靶点。
